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PTPN22 Is a Critical Regulator of Fcγ Receptor–Mediated Neutrophil PTPN22 Is a Critical Regulator of Fcγ Receptor−Mediated Neutrophil Activation Sonja Vermeren, Katherine Miles, Julia Y. Chu, Donald Salter, Rose Zamoyska and Mohini Gray This information is current as of October 3, 2021. J Immunol 2016; 197:4771-4779; Prepublished online 2 November 2016; doi: 10.4049/jimmunol.1600604 http://www.jimmunol.org/content/197/12/4771 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/11/01/jimmunol.160060 Material 4.DCSupplemental References This article cites 53 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/197/12/4771.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 3, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 The Authors All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology PTPN22 Is a Critical Regulator of Fcg Receptor–Mediated Neutrophil Activation Sonja Vermeren,* Katherine Miles,* Julia Y. Chu,* Donald Salter,† Rose Zamoyska,‡ and Mohini Gray* Neutrophils act as a first line of defense against bacterial and fungal infections, but they are also important effectors of acute and chronic inflammation. Genome-wide association studies have established that the gene encoding the protein tyrosine phosphatase nonreceptor 22 (PTPN22) makes an important contribution to susceptibility to autoimmune disease, notably rheumatoid arthritis. Although PTPN22 is most highly expressed in neutrophils, its function in these cells remains poorly characterized. We show in this article that neutrophil effector functions, including adhesion, production of reactive oxygen species, and degranulation induced by immobilized immune complexes, were reduced in Ptpn222/2 neutrophils. Tyrosine phosphorylation of Lyn and Syk was altered in Ptpn222/2 neutrophils. On stimulation with immobilized immune complexes, Ptpn222/2 neutrophils manifested reduced activa- Downloaded from tion of key signaling intermediates. Ptpn222/2 mice were protected from immune complex–mediated arthritis, induced by the transfer of arthritogenic serum. In contrast, in vivo neutrophil recruitment following thioglycollate-induced peritonitis and in vitro chemotaxis were not affected by lack of PTPN22. Our data suggest an important role for PTPN22-dependent dephos- phorylation events, which are required to enable full FcgR-induced activation, pointing to an important role for this molecule in neutrophil function. The Journal of Immunology, 2016, 197: 4771–4779. http://www.jimmunol.org/ eutrophils are the most abundant peripheral blood degradative enzymes and other inflammatory mediators (3). The leukocytes in humans. As part of the innate immune ensuing release of reactive oxygen species (ROS) and proteases N system, they provide an immediate response to infection degrades articular cartilage, whereas secreted chemokines attract or injury. Neutrophils are rapidly activated by a variety of stimuli, further immune cells into the joint, driving chronic inflammation including bacterial peptides, complement, and immune complexes (4). Thus neutrophilic inflammation forms a crucial part of the (ICs). Autoimmune diseases, including rheumatoid arthritis (RA), inflammatory response, which needs to be resolved in a timely are associated with the generation of ICs that accumulate in sy- manner to minimize host damage. novial fluid or are deposited on articular cartilage surfaces. They Protein tyrosine phosphatase nonreceptor 22 (PTPN22) is a engage and activate neutrophils via FcgRs (1, 2). Severe inflam- leukocyte-restricted phosphatase associated with an increased by guest on October 3, 2021 mation follows neutrophil degranulation, releasing a plethora of risk in a range of autoimmune diseases, notably RA. The single missense nucleotide polymorphism (SNP) C1858T encoding an *Medical Research Council/University of Edinburgh Centre for Inflammation Re- R620W substitution is the single most important non-MHC gene search, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom; contributor to RA susceptibility, and the second most important †Institute for Genetics and Molecular Medicine, Edinburgh EH4 2XU, United King- dom; and ‡Institute of Immunology and Infection Research, Ashworth Laboratories, for juvenile idiopathic arthritis according to candidate gene and University of Edinburgh, Edinburgh EH9 3FL, United Kingdom genome-wide association studies (5, 6). Although expression of ORCIDs: 0000-0002-8460-0884 (S.V.); 0000-0002-4451-4375 (D.S.); 0000-0001- PTPN22 is highest in the neutrophil (7), its function in these 9816-2638 (R.Z.); 0000-0002-7622-214X (M.G.). myeloid cells remains largely unknown. In T cells, PTPN22 has Received for publication April 6, 2016. Accepted for publication October 9, 2016. been shown to suppress TCR signaling, for instance, by dephos- Work in M.G.’s laboratory was supported by Arthritis Research UK (Grant 20035) and phorylating key tyrosine residues within the activation loops of the the Medical Research Council (Grant MR/J009555/1). Work in S.V.’s laboratory was Src family kinases (SFKs) Lck and Fyn and the TCR adapter Zap- supported by a University of Edinburgh Chancellor’s Fellowship, a Wellcome Trust Institutional Strategic Support Fund award, and a Medical Research Council studentship. 70. At least in T cells, PTPN22 cooperates with the C-terminal Src S.V. and M.G. initiated the study and designed the experiments; S.V., K.M., and kinase; their physical interaction is critical to their synergistic J.Y.C. performed experiments; S.V., K.M., J.Y.C., D.S., and M.G. analyzed experi- regulatory function. On a protein level, the disease-associated ments and interpreted the data; R.Z. provided experimental tools and advice. S.V., M. G., and R.Z. wrote the manuscript. R620W variant (R619W in the mouse) affects one of four proline- rich regions in the C terminus of PTPN22. This disrupts PTPN22 Address correspondence and reprint requests to: Sonja Vermeren and Mohini Gray, Med- ical Research Council/University of Edinburgh Centre for Inflammation Research, Queen’s binding to C-terminal Src kinase (8, 9). Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, U.K. E-mail The K/B3N serum transfer arthritis model of arthritis is in- addresses: [email protected] (S.V.) and [email protected] (M.G.) duced by administration of arthritogenic serum from arthritic The online version of this article contains supplemental material. KRN 3 NOD donors. This bypasses the need for an adaptive Abbreviations used in this article: IC, immune complex; ko, knockout; PKB, protein immune system–driven break in self-tolerance. It results in a kinase B; PTPN22, protein tyrosine phosphatase nonreceptor 22; RA, rheumatoid arthritis; ROS, reactive oxygen species; SFK, Src family kinase; SNP, single missense transient, but rapidly evolving, inflammatory arthritis that repro- nucleotide polymorphism; Syk, spleen tyrosine kinase; TEM, transendothelial migra- duces many of the hallmarks of RA (10, 11). In combination with tion; WT, wild-type. a range of experimental approaches, including genetic lineage This is an open-access article distributed under the terms of the CC-BY 3.0 Unported depletion and reconstitutions, this disease model has helped to license. elucidate the important contribution of innate immune cells, no- Copyright Ó 2016 The Authors 0022-1767/16 tably neutrophils, to the effector phase of RA (12–14). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600604 4772 PTPN22 REGULATES NEUTROPHIL ACTIVATION In this article, we present an analysis of PTPN22 function in the faces were treated identically, but not incubated with Ab. Some assays neutrophil, concentrating on FcgR signaling owing to its prominent were carried out with insoluble ICs, which had been generated as described role in autoimmune diseases. By performing functional assays with (19). Human fibrinogen (150 mg/ml), polyRGD (20 mg/ml), or, as a con- trol, heat-inactivated FCS was adsorbed onto tissue culture–grade plastics isolated neutrophils from PTPN22-deficient mice and by analyzing overnight at 4˚C and for 3 h at room temperature, respectively. All surfaces inflammation in K/B3N serum transfer arthritis, we demonstrate were extensively washed with PBS prior to performing any assays. that PTPN22 regulates FcgR neutrophilic inflammation. ROS production assays Materials and Methods ROS production was measured by chemiluminescence in a Synergy H1 plate reader (BioTek) using a luminol-based assay in luminescence grade 96-well Unless otherwise stated, materials were obtained from Sigma. plates (Nunc; Thermo Scientific) essentially as previously described (20). Abs Measurements were started immediately following cell stimulation, and light emission was recorded. Data output was relative light units per second. Abs directed against phosphotyrosine (PY1000), phospho–spleen tyrosine
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